Monitor and system for monitoring an organism

ABSTRACT

Provided is a monitor for monitoring the condition of the interior of a living organism from the surface of the living organism. The monitor is provided with: a probe which includes an observation window and is attached to the organism surface; a unit which irradiates, with a laser, at least a portion of an observation region; a unit which detects scattered light resulting from the laser irradiation; a Doppler analysis unit and a SORS analysis unit which narrow down the observation spots to a first observation spot; and a CARS analysis unit which obtains the optical spectrum for at least one component, and outputs first information indicating the condition of the organism interior on the basis of the intensity of the spectrum.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/687,729, filed on Nov. 19, 2019, which is a continuation ofU.S. Ser. No. 14/888,093, filed on Oct. 30, 2015, which is a nationalstage application of PCT/JP2014/002416, filed on May 2, 2014, and whichclaims the priority JP Application No. 2013-096921 which was filed onMay 2, 2013. U.S. Ser. No. 16/687,729, U.S. Ser. No. 14/888,093,PCT/JP2014/002416; and JP Application No. 2013-096921 are allincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a monitor for monitoring the internalstate of an organism and a system that provides physiologically activesubstances based on information from a monitor.

BACKGROUND ART

Japanese Laid-Open Patent Publication No. 2007-192831 discloses adiagnostic kit capable of avoiding the need for invasive tests or theuse of a blood marker in the measurement of glucose regulation. Suchdiagnostic kit is a diagnostic kit for measuring blood sugar regulationin a subject and includes a predetermined amount of enriched ¹³C glucoseand a respiration sampling container. The diagnostic kit includes aplurality of respiration sampling containers in one embodiment, is usedfor diagnosing diabetes in another embodiment, and is used fordiagnosing insulin resistance in yet another embodiment.

DISCLOSURE

Although breath analysis is non-invasive, it is difficult tocontinuously monitor the state of an organism.

One aspect of the present invention is a monitor that monitors a stateof an organism (living organism) internal part from a surface of theorganism. The monitor includes: a probe including an observation windowattached to the surface of the organism; a unit that emits a laser ontoat least part of an observation region on the surface of the organismaccessed via the observation window; a unit that detects scattered lightcaused by emission of the laser from each of a plurality of observationspots that are either intermittently dispersed in two dimensions in theobservation region or are continuously formed so as to scan theobservation region; a unit that limits, based on the scattered lightobtained from the plurality of observation spots, from the plurality ofobservation spots to first observation spots where it is evaluated thatscattered light including information on a target part of the organisminternal part is obtained; and a unit that acquires spectra of at leastone component from the first observation spots or peripheries of thefirst observation spots and outputs first information showing the stateof the organism internal part based on intensities of the spectra.

It is desirable for the monitor to further include a unit that acquiresspectra of a first component for a plurality of parts at differentdepths from the surface of the organism at the first observation spotsor the peripheries of the first observation spots and further limits orupdates the first observation spots based on the intensity of thespectra of the first component.

Another aspect of the present invention is a control method for a systemincluding a monitor that monitors a state of an organism internal partfrom a surface of the organism. The monitor includes: a probe that setsa plurality of observation spots that are dispersed in two dimensions atfirst intervals on the surface of the organism; a unit that emits alaser onto the surface of the organism so that scattered light isoutputted from each of the plurality of observation spots; and a unitthat detects scattered light from the plurality of observation spots.The control method includes the following steps.

1. Acquiring scattered light from each of the observation spots in theplurality of observation spots and finding first observation spotsrelating to subcutaneous blood vessels out of the plurality ofobservation spots using a laser Doppler effect.2. Acquiring spectra of a first component of a plurality of parts atdifferent depths from the surface of the organism at the firstobservation spots or peripheries of the first observation spots anddetermining, based on intensities of the spectra of the first component,a target part below the surface of the organism.3. Outputting first information showing the state of an internal part ofthe organism based on the intensities of the spectra of at least thefirst component at the target part.

It is desirable for the control method to further include the followingstep.

4. Acquiring spectra of the first component for a plurality of parts atdifferent depths from the surface of the organism at the firstobservation spots or the peripheries of the first observation spots andfurther limiting or updating the first observation spots based on theintensity of the spectra of the first component.

It is possible to analyze compounds present in bodily fluids, such asblood, and subcutaneous tissues using spectroscopy technologies such asnear-infrared spectroscopy and Raman spectroscopy, and to furtheranalyze biochemical substances, cellular components, and the like inbodily fluids based on the analysis result. This means that it isdefinitely possible to acquire organism information by spectroscopy.However, the concentration of biochemical substances and cellcomposition differ at different parts of the organism. This means thatthe acquired information will include information of various structuresbelow the surface of the organism, the target information may be buriedin other information and noise, and it may be difficult to estimate thestate of the organism.

With the monitor and control method described above, a plurality ofobservation spots are set in an observation region on the surface of anorganism that can be accessed via the observation window of the probe.In addition, instead of using all data from the plurality of observationspots, spectra are acquired by locking onto some out of the plurality ofobservation spots using the unit that limits, and first informationshowing information on an internal part of the organism is outputtedbased on such data. Accordingly, since it is possible to selectivelyacquire information relating to a limited part below the surface of theorganism, it is possible to avoid having the target information buriedin other information or noise.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram showing a health management system.

FIG. 2 is a block diagram showing a monitor.

FIG. 3 is a diagram showing an observation region and observation spots.

FIG. 4 is a diagram showing Raman spectra.

FIG. 5 is a block diagram showing an event recognizing module.

FIG. 6 is a diagram showing changes in glucose.

FIG. 7 is a flowchart showing the operation of the health managementsystem.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

An example case that has subcutaneous capillary vessels as a target andacquires information including an amount of a component (for example,glucose) flowing through the capillary vessels by acquiring spectra isdescribed below.

The monitor according to the present invention sets a plurality ofobservation spots in an observation region on the surface of an organism(living organism, living body) that is accessible via an observationwindow of a probe. First, based on the scattered light obtained from theplurality of observation spots, a limiting unit first limits to, orlocks onto, some of the observation spots where it is estimated thatinformation on a target part of an organism internal part (a part ofinternal of a living organism) can be obtained as first observationspots. If the target part is a capillary vessel in the organism internalpart, it is possible to focus on the spectra of laser Doppler effectsincluded in the scattered light and to lock onto an observation spot asa first observation spot according to whether blood flow is observed atthe observation spot. The target part is not limited to capillaryvessels and in the case of lymph glands, it is possible to focus on thespectra of a component detected with the highest intensity when carryingout spectroscopic analysis of components included in lymph glands and tolock onto an observation spot as a first observation spot according towhether such component is observed at the observation spot.

Instead of merely finding a two-dimensional profile when locking ontothe first observation spots, the limiting unit may find athree-dimensional profile that includes a profile in the depthdirection. For capillary vessels, it is possible to calculate a profilein the depth direction from the blood flow component included in thelaser Doppler effects using a mathematical model. When measuring Ramanspectra, it is possible to use Spatially Offset Raman Spectroscopy(SORS).

It is assumed that the first observation spots where the blood flow of acapillary vessel are observed will be positioned corresponding above ornear the capillary vessel. A unit that outputs first information that isorganism information locks onto the first observation spots orobservation spots in the periphery of or about the first observationspots, acquires spectra of at least one component, and outputs firstinformation that shows the state and/or conditions of the organisminternal part based on the intensity of the spectra.

With this monitor, it is effective to provide a unit that acquiresspectra (spectrums) or a spectrum of a first component at a plurality ofparts for different depths from the surface of the organism at the firstobservation spots or the peripheries thereof and further limits orupdates the first observation spots based on the intensity of thespectra or the spectrum of the first component. It is possible toacquire spectra of a plurality of parts at different depths from thesurface of the organism using spectrometry and to determine, from theintensity of the first component included in the spectra, the spectra orthe spectrum of the target part. As one example, if it is desirable todetect the concentration of biochemical substances present in bloodvessels, for a human subject, the vicinity of the organism surface isformed by the skin (epidermis) that forms the surface, the dermis, andsubcutaneous tissues, with blood vessels (capillary vessels) often beingpresent in the dermis or the subcutaneous tissues. However, the distancefrom the surface to the blood vessels differs according to the bodypart, also differs from patient to patient, and can also differaccording to the patient's posture at such time.

With this monitor, by determining a spectrum where the intensities ofthe components present in the largest quantities in blood is the highestout of the spectra at different depths, it is possible to determine aspectrum of blood. By determining the intensities of one or a pluralityof components included in a blood spectrum, it is possible to outputfirst information showing the state of an internal part of an organismbased on concentrations in blood. The target part is not limited to ablood vessel and may be subcutaneous fat or a lymph node or glands, andit is possible to generate first information showing the state of anorganism internal part based on components of a plurality of targetparts at different depths. Typical values for clinical biochemicalanalysis obtained from the spectrum of blood are cholesterol, bloodsugar (glucose), glycated hemoglobin (such as HbA1c), AST, ALT,triglycerol, G-GTP, LDH, ALP, adiponectin, and the like.

One simple spectroscopic method for adjusting depth is a confocal Ramananalysis. By using one or more confocal Raman analysis units, it is alsopossible to obtain three-dimensional information on components or cellspresent at a target part. Although the incident light for spectrometrymay be LED light or light with a comparatively wide waveband, laserlight of a narrow waveband is desirable. Using a tunable laser whosewavelength can be changed as a light source makes adjustment of deptheasier and by carrying out resonance Raman spectroscopy, it is alsopossible to obtain a more precise spectrum of the target part.

Another example of a spectroscopic analysis method that can generate aprofile in the depth direction is spatial offset Raman spectroscopy(SORS). In addition, as a method which can produce a profile in thedepth direction with high precision, the present inventors has proposedthe acquisition of a CARS spectrum that is spatially offset bycontrolling the incident angle (irradiation angle) of the pump light orStokes light used in CARS (Coherent Anti-stokes Raman Spectroscopy(scattering)).

The plurality of observation spots may be set by selectively emitting(irradiating) a laser onto a plurality of observation spots or scatteredlight may be selectively acquired from each of a plurality ofobservation spots. Accordingly, the probe may include an output unitthat selectively guides the laser from the unit that emits to respectivespots in the plurality of spots. The probe may include an input unitthat guides the scattered light from the respective spots in theplurality of observation spots to the unit that detects. One example ofthe output unit and the input unit is a mirror or a group of mirrors(MD, Micro-mirror Device) that is formed by a MEMS or a micromachine. Itis possible to form one or a plurality of laser spots intermittently orcontinuously inside the observation region and possible to form a largenumber of observation spots.

Another example of the output unit and the input unit is a combinationof an optical member that forms multiple focal points, such as photoniccrystal fiber (PCF),

micro-structured fiber, Holey fiber or a bundle fiber, and a shuttermatrix formed by a MEMS or a micromachine or an MD. It is possible toform one or a plurality of laser spots intermittently inside theobservation region and possible to form a large number of observationspots.

It is desirable for the output unit and the input unit to be capable ofsetting a plurality of observation spots in the observation region atintervals of 1 to 1000 μm. It is even more preferable for the pluralityof observation spots to be set at intervals of 10 to 100 μm in theobservation region. The average size of subcutaneous tissues is severalμm to several tens of μm, and it is preferable for the monitor to have aresolution of several hundred μm or smaller.

It is desirable for the probe to be tightly attached to the skin.Although it is possible to attach to the skin via a fluid such as gel,in view of user convenience and comfort, it is desirable for theobservation window to be tightly attached to the surface of the skin viaa diffusive porous membrane. Examples of diffusive porous membranes aremembranes made of PDMS (polydimethylsiloxane) and hybrid silica.

By combining this monitor with a delivery unit that provides aphysiologically active substance to the organism based on the firstinformation obtained from the monitor, it is possible to provide amedication system. Such system is used to treat patients, to managephysical health, for rehabilitation, and the like. The physiologicallyactive substance may be a biological material or a synthetic material,and represents a single substance or group of chemicals that has aphysiological effect or a pharmacological effect on the organism.Physiologically active substances include vitamins, minerals, oxygen,and hormones, with one example of a hormone being insulin.

It is desirable for this system to include a behavior (movements)monitoring unit that acquires or predicts an external state (condition)of the organism. It is desirable for this system to further include aunit that controls an amount or type of physiologically active substanceprovided to the organism from the delivery unit according to information(second information) from the behavior monitoring unit in addition tothe first information. By predicting the internal state (condition) ofthe patient in the near future from the patient's life rhythms andbehavior patterns and/or predicting future changes in the organism fromwhether the patient is actually having a meal or exercising, it ispossible to carry out prior control (advanced control) of the type andamount of physiologically active substances to be administered inaccordance with the present state of the organism. This means that it ispossible to control the type and amount of a physiologically activesubstance so that the state or conditions of the patient matches his/herbehavior.

In addition, it is desirable for the system to include a unit thatoutputs the first information and an operating state of the deliveryunit to outside (external). Via the system, it is possible for a doctor,nurse, or the like to remotely monitor a patient.

The control method for a system that includes the above monitordescribed in this specification can be provided as a program or aprogram product via the Internet or by being recorded on a suitablerecording medium. This control method for a system may be provided as amethod for monitoring the state of an organism internal part from thesurface of the organism using spectrometry. This method may be providedas a method for treating a patient, may be provided as a method thatmanages the physical health or conditions of a user, or may be providedas a method for pre-emptively avoiding seizures or the like.

When the system includes a delivery unit that provides a physiologicallyactive substance to the organism, it is desirable for the control methodto further include a step of selecting a physiologically activesubstance and an amount to be delivered by the delivery unit based onthe first information.

When the system further includes a behavior monitoring unit thatacquires or predicts an external state of the organism, it is desirablefor the step of selecting to include selecting the amount and/or type ofphysiologically active substance delivered by the delivery unit based oninformation on the external state in addition to the first information.

FIG. 1 shows, by way of a block diagram, the overall configuration of anon-invasive health and vitality control platform (control or adjustmentsystem). This system 1 includes a sensor platform 10, an analysis engine120, a drug delivery unit 130, and an event tracking unit 140. Note thatalthough the system 1 that manages the health of a diabetic patient soas to keep the patient alive and to enable the patient to live a healthyand active life is described as an example in the following description,the disease to which the system 1 can be adapted as a platform is notlimited to diabetes.

The sensor platform (monitor) 10 is capable of continuously andnon-invasively monitoring the amount of glucose in the blood of adiabetic patient. One example of the sensor platform 10 is a variablewavelength FTIR-Raman spectroscopic analysis unit. The sensors mountedin the sensor platform 10 do not need to be of a single type and it ispossible to use a plurality of types or to include a plurality ofsensors of the same type. As examples, it is possible to collectivelyattach one or a plurality of types of sensors such as an infraredspectroscopic analysis apparatus, a near-infrared spectroscopic analysisapparatus, a mass spectrometry apparatus, and an ion mobility sensor tothe surface of the organism, or to attach such sensors so as to bedistributed on the surface of the organism.

The sensors included in the monitor 10 use MEMS technology or the likeand are compact and lightweight to the extent that when such sensors areattached to a human or other organism (body), the life and activity ofthe subject are barely obstructed. The sensors also need to have lowpower consumption so as to operate for an extended period using alightweight battery. The power supply may be a small battery, agenerator that uses external energy, such as a solar cell, a generatorthat generates power using body temperature, another biologicalreaction, or the activity of the organism, or may be a combination ofthe above.

The monitor 10 needs to have high precision and to be equipped with anautomatic calibration function. The automatic calibration function has afunction for automatically finding the measurement target part of theorganism internal part from the surface of the organism andautomatically tracking or rediscovering information from the target partwithout being affected by activity or the like of the organism (livingorganism).

Information (organism information) 150 for which measurement of adiabetic patient by the monitor 10 is desirable includes the glucoseconcentration in the blood, glycated hemoglobin concentration (HbA1cconcentration) in the blood, glycated albumin concentration in theblood, blood pressure, blood oxygen content, cancer markers, and otherfactors related to health and life support.

FIG. 2 shows a Raman spectroscopic analysis unit 11 as an example of themonitor 10. This unit 11 includes an optical engine 20, a tunable laserengine 30, a detector 40, and a signal processing engine 50. Suchcomponents are packaged as chips, and the unit 11 is capable of beingattached to the surface (skin) 2 of the organism (human body) 7 in astate where such chips are stacked.

The optical engine 20 is a MEMS optical chip and includes a probeincluding an observation window 21 attached to the skin 2, a unit 25that emits (irradiates) a laser onto at least part of an observationregion 3 of the skin 2 accessed via the observation window 21, and aunit 27 that detects scattered light produced by the emitted(irradiated) laser either intermittently so as to be distributed in twodimensions in the observation region 3 or from each of a plurality ofobservation spots continuously formed by scanning the observationregion.

The laser emission unit (primary optical system) 25 is compatible withCARS and includes a first optical path 25 a that guides Stokes light 31of an angular frequency ωs obtained from the tunable laser engine 30 anda second optical path 25 b that guides pump light 32 of an angularfrequency ωp obtained from the tunable laser engine 30. The firstoptical path 25 a and the second optical path 25 b include a polarizerP, a half-wave plate HWP, a ¼ wavelength plate QWP, and the like. Thelaser emission unit 25 combines the Stokes light 31 and the pump light32 using a dichroic beam combiner BC and emits laser light to theobservation region 3 via the probe 23.

The laser engine 30 is a laser chip or an LED unit of a chip type thatemits laser light of a plurality of wavelengths. As a variablewavelength laser engine, it is possible to use a Littrow laser engine, aLittman laser engine, or the like. As the laser engine 30, an enginecapable of supplying variable wavelength Stokes light 31 and variablewavelength pump light 32 is especially desirable. One example of thewavelength range of the Stokes light 31 is 1000 to 1100 nm, with 900 to1450 nm being more preferable. One example of the wavelength range ofthe pump light 32 is 700 to 800 nm. The laser engine 30 may generatelaser light of such wavelength ranges using a combination of a pluralityof light source units.

A detection unit (secondary optical system) 27 includes a beam separatorBS that separates the anti-Stokes light with the angular frequency wassupplied from the probe 23 and an optical path 27 a that suppliesscattered light (secondary light) 28, which is obtained from a pluralityof observation spots formed so as to be distributed in two dimensions inthe observation region 3, to the light detector 40. The detection unit27 may include a lens L for collecting the scattered light 28 into thedetector 40, a laser block filter, a diffraction grating, and the like.The detection unit 27 may include a flip mirror that divides andsupplies the scattered light 28 to different types of detector, forexample a CCD and a photodiode.

The light detector 40 may be a sensor where detection elements such asCCDs or CMOS are laid out in two dimensions. The light detector 40 maybe a photodiode, with an InGaAs photodiode that has a fast responsespeed, low noise, and superior frequency characteristics being suitable.In particular, if the probe 23 is provided with a high resolutionselecting function for the observation spots, a selecting function forthe observation spots on the light detector 40 side may be unnecessaryor may be a low resolution selecting function. Accordingly, it ispossible to use a photodiode as the detector 40 and to output a signalwith low noise.

The probe 23 includes an output unit 23 a that forms a plurality ofobservation spots in the observation region 3 that can be accessed viathe observation window 23 and an input unit 23 b capable of selectivelyacquiring the scattered light 28 from the plurality of observationspots. The probe 23 uses an MD unit where MEMS type polygon mirrors areintegrated as the output unit 23 a, uses a combination of an MD unit andmulti-fibers as the input unit 23 b, and is designed so as to be capableof selectively acquiring the scattered light 28 from many observationspots in a state where there is no crosstalk.

FIG. 3 shows how a plurality of observation spots 5 are set in theobservation region 3. In this example, 12 by 12 observation spots 5 areset with a pitch of 50 μm in a 600 μm by 600 μm observation region 3.The size of the observation region 3, and the pitch and number of theobservation spots 5 are mere examples and are not limited to thesevalues. The observation spots 5 do not need to have a regular pitch andmay be continuously set using the MD unit. A high degree ofreproducibility is required for the respective positions of theobservation spots 5. It is also desirable for the pitch of theobservation spots 5 to be sufficiently capable of detecting the size ofthe capillary vessels 8 (which for example have a diameter of several μmto several tens of μm) to be detected and to be capable of selectivelyacquiring information on the capillary vessels 8. Accordingly, the pitchof the observation spots 5 should preferably be around 1 to 1000 μm andmore preferably around 10 to 100 μm.

The optical engine 20 may be provided with a function as 3D confocalRaman microscopy.

The signal processing engine 50 that controls the optical engine 20includes a laser Doppler analyzing unit 51, a SORS analyzing unit 52, aCARS analyzing unit 53, a 3D profile unit (3D profiler) 54, a memory 55,and an organism information generating unit 56. The Doppler analyzingunit 51 and the SORS analyzing unit 52 function as the unit that limits,based on the scattered light 28 obtained from the plurality ofobservation spots 5, to the first observation spots 5 a out of theplurality of observation spots 5 where it is determined or evaluatedthat scattered light 28 including information on capillary vessels 8that are the target parts inside the organism 7 is obtained.

Based on the output of the laser Doppler analyzing unit 51 and the SORSanalyzing unit 52, the 3D profiler 54 locks onto the first observationspots 5 a that two-dimensionally cover the capillary vessels 8 and formsa profile in the depth direction for the first observation spots 5 a. Bydoing so, a three-dimensional profile 57 of the capillary vessels 8related to the observation region 3 is formed and stored in a memory 55.The three-dimensional profile 57 of the capillary vessels 8 is notlimited to a single profile. The three-dimensional profile 57 may differevery time the probe 23 is placed, and may differ over time duringprobing, due to a change in posture or the like.

The CARS analyzing unit 53 functions as a unit that acquires spectra ofat least one component from the first observation spots 5 a and/orobservation spots in the periphery of or about the first observationspots and outputs first information 58 showing the state (conditions) ofthe internal part of the organism 7 based on the intensity of thespectra. In addition, the CARS analyzing unit 53 functions as a unitthat acquires spectra of a first component out of a plurality of partswith different depths from the organism surface 2 at the firstobservation spots 5 a and/or the peripheries thereof and verifies thefirst observation spots 5 a and further limits or updates the firstobservation spots 5 a as necessary based on the intensities of thespectra of the first component.

The organism information generating unit 56 generates and outputsorganism information 59 including the information 58 obtained from theCARS analyzing unit 53.

The CARS analyzing unit 53 in the present embodiment is equipped with afunction as a SORS and, by emitting one out of the Stokes light 31 andthe pump light 32 (for example, the Stokes light 31) at one of the firstobservation spots 5 a and controlling the angle of one of the DM of theoutput unit 23 a, emits the pump light 32 at a different angle to theStokes light 31. The scattered light 28 of such laser lights is acquiredat the input unit 23 b that has superior positional selectivity(resolution) at observation spots 5 that are offset from the positionswhere the laser light is incident. By doing so, it is possible to obtainCARS spectra from a structure with different positions in the depthdirection.

If the laser engine 30 is compatible with confocal Raman microscopy, itis possible to change the focal position of the laser in the depthdirection. This means that it is possible to obtain a 3D Raman spectrumof an organism internal part, that is, subcutaneous tissues, from theorganism surface (skin surface) 2.

If Raman spectra of blood flowing in a blood vessel are included in thedifferent Raman spectra in the depth direction, it is possible to verifya 3D profile 57 obtained in advance. It is possible to determine whethera spectrum is a Raman spectrum of blood by selecting a Raman spectrumcomponents (spectrum peaks) of components that have the highestconcentrations in blood or the lowest concentrations in blood. Forexample, glucose is highest in blood vessels compared to subcutaneoustissues and dermis, so that it is possible to determine the position ofa blood vessel by analyzing CARS spectra or 3D Raman spectra based onglucose concentration. In place of glucose, or in addition to glucose,it is possible to determine the positions of blood vessels by focusingon the Raman spectra of components that are mainly included in bloodvessels such as the hematocrit which includes blood cells (white bloodcells, red blood cells) or albumin.

If the position of a blood vessel (the blood vessel depth) can bedetermined, the Raman spectra at such position will reflect thecomponents of blood, and it will be possible to continuously obtaininformation (“blood component information”, “organism internal partinformation”, or “first information”) on the concentration of othercomponents included in blood, for example, information on bloodcomponents such as glycated red blood cell concentration, in real timeor at intervals of a minimal sampling time from the Raman spectra whosepositions have been established. The distance (depth) and the positions(angles) between the monitor (sensor platform) 10 attached to thesurface of the organism and the capillary vessels 8 will changedepending on the posture and movement of the human body. For thisreason, it is desirable to regularly repeat a process that finds thepositions of blood vessels.

FIG. 4 shows a comparison between a Raman spectrum of glucose (brokenline) and a Raman spectrum obtained from bovine blood (solid line).Raman shifts of glucose appear at around 400 cm⁻¹ and 1100 cm⁻¹, and arealso observed in bovine blood. Accordingly, it can be understood that itis possible to measure the glucose concentration in blood from a Ramanspectrum. Note that the spectra shown in FIG. 4 are spontaneous Ramanscattering.

When attaching the probe 23 to the organism surface (skin) 2, it isdesirable for the observation window 21 to tightly adhere to the skin 2that is the surface of the organism with no gap and also for as littlemoisture as possible to be present between the observation window 21 andthe skin 2. Although it is possible to measure using a means such asadjusting the laser power even when a gap or moisture is present, it isdesirable to minimize such amounts to acquire information with highprecision.

In the present embodiment, the probe 23 is placed in tight contact withthe skin 2 via a diffusive porous membrane 45. Although the presence ofmoisture (sweat) due to dermal respiration acts as an obstacle toobtaining a Raman spectra including information on the organism internalpart, by providing the diffusive porous membrane (transmissive membrane)45 between the probe 23 and the skin 2, it is possible to continuouslyrelease moisture to the outside. The diffusive porous membrane 45transmits the laser light 31 and 32 and the scattered light 28 andbarely obstructs the observation described above. Since the diffusiveporous membrane 45 is also elastic, the diffusive porous membrane 45 iscapable of suppressing the production of a gap between the skin 2, evenwhen the person moves. The diffusive porous membrane 45 may be stuckonto the probe or may be stuck onto the skin. Examples of the diffusiveporous membrane 45 are PDMS (polydimethylsiloxane) and hybrid silica.

PDMS is one example of a polymer membrane material where the distancebetween polymer chains is large and therefore exhibits a high gaspermeability coefficient. Accordingly, PDMS functions as a porousmembrane with a fine aperture diameter and has been reported to behydrophobic, have a high affinity to organic liquids, and to havesuperior selective permeability. Hybrid silica is a microporousorganic-inorganic hybrid membrane with an average aperture diameter of0.1 to 0.6 nm, uses silica that is hydrothermally stable up to at least200° C. in several types of media as a base, and can be manufacturedusing short-chain crosslinked silane in a sol-gel process. It has beenreported that hybrid silica is suited to the separation of gases and theseparation of water and other small molecule compounds from variousorganic compounds, such as low molecular weight alcohols. The heatresistance is also high compared to PDMS, which makes hybrid silicasuited to high temperature applications, for example, concentrationwhere accumulation occurs at low temperature and releasing occurs athigh temperature. The diffusive porous membrane 45 is not limited tosuch materials. It is also possible to interpose a semi-fluid, such as agel, with the same functions in place of the diffusive porous membrane45.

The monitor 10 that is the sensor platform may include, in addition toor in place of the Raman spectroscopic sensor 11, an ion mobility sensor(IMS) or a mass spectrometry sensor (MS) that analyzes components indermal respiration. If the sensor platform 10 is a distributed-typesensor, an ion mobility sensor or mass spectrometry sensor for analyzingbreath may be attached to the vicinity of the nostrils or inside thenostrils. Information from a plurality of sensors that are disposed in adistributed manner can be collected wirelessly or using wires.

Returning to FIG. 1 , the analysis engine 120 analyzes the organisminternal part information (information of interior of body) obtained bythe monitor (sensor platform) 10 in combination with organism externalinformation (information of exterior of body) obtained from the eventtracking unit 140 and introduces physiologically active substances intothe organism (human body) using the drug delivery unit 130.

It is desirable for the drug delivery unit (delivery unit) 130 to beautomated, non-invasive and to be equipped with a plurality of drugintroducing paths (channels), and to be capable of being easily attachedto or stuck onto the organism (human body) 7. One example is anon-invasive insulin pump or injector that utilizes ultrasound using aMEMS, a field effect transistor, or nano-jets. Examples of prescriptiondrugs 152 for diabetic patients are basal insulin and bolus insulin.

The drug delivery unit 130 may be attached to the surface of the bodyalongside the monitor 10. There is the risk that the physiologicallyactive substance introduced into the body by the drug delivery unit 130will affect the organism internal part information acquired by themonitor 10 before becoming absorbed or diffused in the body as expected.In such case, it is desirable for the drug delivery unit 130 to beattached to a position that is distant from the monitor 10, for exampleon the opposite side of the body. The information paths between the drugdelivery unit 130, the analysis engine 120, and the monitor 10 may bewired or may be wireless and such elements may be connected directly, orindirectly via a computer network.

The event tracking unit 140 that provides the organism externalinformation to the analysis engine 120 may be attached to the body, mayobserve actions of the body from outside, may be included in a serverthat manages the schedule of the patient, or may be a combination ofsuch. A typical example of the event tracking unit 140 is a sensor or asensor group that is capable of being attached to the body. The eventtracking unit 140 includes functions that determine whether the patienthas eaten and the content of meals using information obtained from imagesensors or the like and/or recognize actions taken by the patient (asexamples, has the patient started exercising, is working as normal, issleeping, or is resting) using information obtained from accelerationsensors or the like.

The event tracking unit 140 may be equipped with sensors that acquirethe body temperature of the patient, the humidity of the skin surface,and the temperature, humidity, wind speed, atmospheric pressure and thelike outside the patient. It is also desirable for the event trackingunit 140 to be equipped with a function (learning function) that studieshistorical actions of the patient and is capable of predicting theactions of the patient (such as having a meal, exercise (training),daily business, sleeping, or resting) in the near future, such as acertain time later, one hour later, thirty minutes later, or severalminutes later.

The analysis engine 120 is equipped with a function as a control unit ofthe system 1. The analysis engine 120 further includes a function (eventpredicting function) that predicts events that will dynamically occurfor the patient himself/herself or in the periphery of the patient basedon the organism external information obtained from the event trackingunit 140, a function (static event analyzing function) that considersthe occurrence of normal (every day, routinely or static) events, and anevent recognizing module 60.

The analysis engine 120 further includes a function (dosage estimatingfunction) that considers the organism external information including thepredicted events in addition to the organism internal part informationobtained from the sensor platform 10 and decides and controls the typeand amounts of physiologically active substances (for example, hormonessuch as insulin, prescription drugs, minerals, and nutrients) to beintroduced from the drug delivery unit 130. The analysis engine 120further includes a function (body parameter monitoring function) thatacquires, for the function that decides the types and amounts ofphysiologically active substances, body parameters such as the contentof any prescriptions, size characteristics of the body, and pre-existingconditions (disorders), from a database or the like and a function(calibration function) for calibrating.

The dosage estimating function that decides the types and amounts ofphysiologically active substances to be introduced or administered(dosed, injected) to the body includes a closed loop function thatdecides the types and amounts based on the organism internal partinformation and an open loop function that adds corrections to theoutput of the closed loop function based on a prediction function thatincludes the organism external information.

FIG. 5 shows an overview of the event recognizing module 60. This eventrecognizing module 60 may be provided in the analysis engine 120 or maybe provided in the event tracking unit 140. The event recognizing module60 processes information on real time GCM (Continuous GlucoseMonitoring) obtained from the module 10 using event predictioninformation 62 and generates an event recognition 63 for controlling themedication (drug delivery) unit 130. The event prediction information 62is generated based on information 65 showing that a meal or food hasbeen taken, information 66 about everyday activities (daily life, dailybusiness, daily work) being done, information 67 about sleep, and thelike, which are obtained by the event tracking unit 140 or the like.

The analysis engine 120 further includes a function 68 that decides thetypes and amounts of physiologically active substances in accordancewith an application or applications provided by a third party using anonline store 154 or the like. Examples of applications provided by theonline store 154 include a program for diabetic patients, a dietmanagement program, a heart disease program, a stress monitoringprogram, a lifestyle management program, a prevention-diagnosis program,and an adapted diagnosis program. Here, myocardial infarction, cerebralinfarction, liver dysfunction, renal dysfunction, and hyperlipidemia canbe given as examples of diseases that can be determined or evaluated bythe sensor platform 10 and treated or subjected to emergency responseusing physiologically active substances.

The analysis engine 120 also includes a function that exchangesinformation with a cloud service 156. The cloud service 156 includes aservice that enables doctors or nurses and also family members or thelike to monitor a patient online, and includes services such as onlinemonitoring, a service that determines the type and amounts of medicationby overriding events, a function that generates an event database, and aservice that allows remote monitoring.

The analysis engine 120 can be realized using computer resourcesincluding a CPU and memory, may be an LSI or an ASIC, and also may berealized using a chip in which circuits can be reconfigured.

FIG. 6 shows an example of glucose changes in blood. The solid lineshows a case where glucose in blood is investigated using some methodand insulin is administered. When the glucose concentration in blood ismeasured using a puncture sensor (tap sensor), a delay (sensor lag) isproduced in the measurements. Due to the administration (dosing) 77 ofinsulin being too late or too early, or the amount of insulin being toomuch or too little as a result, there is the risk of the glucose amount76 reaching a hyperglycemic state 78 or a hypoglycemic state 79. In theworst case scenario, irreparable damage can be caused to the body, whichmay even lead to death. To avoid such situation, it is necessary topreemptively avoid the occurrence of states where the blood sugar levelof a diabetic patient is changeable, and necessary for the patient tolive with various limitations, such as avoiding acute exercise andtaking regular meals and ingesting only a predetermined amount ofcalories.

On the other hand, in the health management system 1 according to thepresent embodiment, glucose in blood is continuously measured in realtime by the monitor 10. Accordingly, it is possible to precisely controlthe administered amount of insulin with respect to the glucoseconcentration which is measured continuously. In addition, the eventrecognizing module 60 detects the occurrence of events (patientactivities) such as exercise and meals and also predicts patientactivities using a daily schedule and the outputs of various sensors.The analysis engine 120 decides the types and amounts of administeredinsulin so as to match the predicted state. This means that it ispossible to control the glucose concentration in blood to a range 75with a narrow width where there is little influence on health. Thismeans that it become possible even for a diabetic patient to play sportsand have meals in the same way as someone of good health conditions.

FIG. 7 shows the major processes of the health management system 1 byway of a flowchart. In step 81, the observation window 21 of the probe23 of the monitor 1 is attached to the surface of the skin 2 via thePDMS 45. In step 82, the Raman spectrum of moisture on the skin 2 in theobservation region 3 visible in the observation window 21 is measured.As one example, it is possible to measure the amount of moisture at thesurface and inside the skin using a confocal method, and it is alsopossible to measure the distance to the skin. In step 83, the output(power) of the laser used in subsequent measurements is adjustedaccording to the amount of moisture at the skin surface and distance tothe skin surface. Since the penetration of the laser will change ifthere is a lot of moisture on the surface of the skin 2 or a gap ispresent between the skin 2 and the observation window 21, it isdesirable to adjust the output power of the laser. It is also possibleto find the amount of moisture on the surface of the skin 2 by measuringthe electrical conductivity (conductivity).

In step 84, the laser Doppler analyzing unit 51 is used to determine theobservation spots 5 a where blood flow is detected out of theobservation spots 5 in the observation region 3 using a laser Dopplermethod. By limiting to or setting the observation spots 5 a where bloodflow is detected, it is possible to specify the positions of capillaryvessels 8 in the observation region 3 and to identify observation spots5 a positioned directly above or in the vicinity of the capillaryvessels 8. As one example, it is possible to emit pump laser light 32with a wavelength of around 800 nm onto the entire observation region 3,to acquire spectra (Rayleigh scattering) of the scattered light 28obtained from the respective observation spots 5, and to determine thepresence of blood flow if a spread of Doppler shift frequencies of lightthat has been scattered by red blood cells is observed in such spectra.The laser light 32 may be separately emitted onto the respectiveobservation spots 5 using the DM module 23 a.

In step 85, the observation spots (first observation spots) 5 a to bemeasured in the following steps are limited (narrow downed) and lockedonto as the measurement targets via the first observation spots 5 a. Instep 86, the 3D profiler 54 generates, from the Doppler shift dataobtained from the locked-onto observation spots 5 a and in accordancewith a mathematical model, a depth profile showing the capillary vessels8 below the observation spots 5 a that have been locked onto.

Next, in step 87, the profiler 54 also verifies the profile in the depthdirection of the observation spots 5 a using the SORS analyzing unit 52.With spatially offset Raman spectroscopy (SORS), by emitting laser lightonto the observation spots 5 a and acquiring the scattered light 28 awayfrom the observation spots 5 a at observation spots 5 in the peripheryof the observation spots 5 a, Raman spectra are obtained from the deeptissues below the skin 2. It is also possible to adjust the incidentangle of the laser and acquire Raman spectra for generating a profile inthe depth direction.

In step 88, once the 3D profile 57 that includes depth profiles usingthe locked observation spots 5 a is obtained, the profiler 54 decidesthe positions in the depth direction to be measured (the target parts)where capillary vessels 8 are likely to be present. By doing so, thethree-dimensional positions of the target parts are decided.

In step 89, the CARS analyzing unit 53 acquires CARS spectra from themeasured positions using coherent anti-stokes Raman spectroscopy (CARS).The CARS analyzing unit 53 emits (incidents, irradiates) a variablewavelength laser as the Stokes light 31 and/or the pump light 32selectively onto the locked observation spots 5 a or the observationspots 5 in the periphery of the locked observation spots 5 a so as tointersect at the set depths. By doing so, from the locked observationspots 5 a, it is possible to acquire the anti-Stokes Raman scatteredlight 28 from components that are present at the set depth and thatmatch the wavelength conditions set by the Stokes light 31 and the pumplight 32. This means that the detector 40 is capable of detecting a CARSspectrum from the tissue at positions below the skin where the capillaryvessels 8 are likely to be present. Accordingly, information on thecapillary vessels 8 is obtained as low noise information without beingdiluted by or averaged with Raman spectra from other tissues.

To supply the scattered light 28 from the individual observation spots 5a to the detector 40, it is desirable to use the input unit 23 bequipped with a combination of multi-fibers capable of formingmultifocal points and a DM or a MEMS type shutter to shut out thescattered light 28 from other observation spots 5.

In addition, by giving the Stokes light 31 and the pump light 32variable wavelengths and limiting or narrowing the emission (incident)position and area to the locked observation spots 5 a or the peripheriesof the observation spots 5 a respectively, positional resolution andwavelength selectivity are unnecessary at the detector 40. This meansthat it is possible to use a photodetector that has a fast responsespeed and high precision. This means that it is possible to supply theStokes light 31 and the pump light 32 as light in short pulses, and asone example, it is possible to supply pulsed light in picosecond orfemtosecond units.

Accordingly, it is possible to preemptively prevent damage to the skin 2by laser light and possible to acquire information from the capillaryvessels 8 continuously for a long time while suppressing the influenceon the body. It is also possible to further reduce the influence of thelaser light on the skin 2 by placing a porous membrane such as the PDMS45 between the system 1 and the skin 2.

In step 90, the CARS analyzing unit 53 extracts information on glucose,hemoglobin HbA1c, and the like from CARS spectra and supplies suchinformation as the first information 58 to the organism informationgenerating unit 56. The organism information generating unit 59aggregates the first information 56 on blood and if necessary,information collected by the profiler 54 in the process of generating a3D profile, and supplies the aggregated information to the analysisengine 120 as the organism internal part information 59.

In step 91, the CARS analyzing unit 53 acquires CARS spectra for whichthe depth set as the measurement target (target part) is changed atfixed intervals. From the glucose concentration included in the Ramanspectra that change in the depth direction (the vertical direction), itis determined whether a depth spectrum of the target part is suitable asthe spectrum of a blood vessel compared to spectra of parts at otherdepths. By doing so, it is possible to always verify the depth profile57. In step 92, when information obtained from a target part is notsuitable as a blood vessel, the processing returns to step 84 and the 3Dprofile 57 is updated and regenerated.

The Raman spectrum component used to verify the depth profile 57 is notlimited to glucose and may be hematocrit, albumin or other componentsuch as that is present in an even higher concentration in a bloodvessel than the periphery tissues.

When acquiring CARS spectra by changing the depth direction, the CARSanalyzing unit 53 may change the angle of the Stokes light 31 or thepump light 32 and acquire CARS spectra at a position that is shifted(offset) from a predetermined observation spot 5 a. By acquiring CARSspectra that have been spatially offset (SOCARS spectra), it is possibleto further improve the precision of the profile in the depth direction.

It is also possible to acquire spectra using resonance Ramanspectroscopy in place of CARS or in addition to CARS. By combining dataof a plurality of Raman spectrometry sensors 11, 3D Raman spectra may beacquired.

In step 90, the analysis engine 120 is capable of acquiring organisminternal part information including all components that can be estimatedfrom Raman spectra which are not limited to glucose and may be chemicalcomponents aside from glucose, cells such as red blood cells, and bloodcomponents such as proteins like albumin and others that are present inblood flowing in blood vessels.

In step 93, the analysis engine 120 also acquires organism externalinformation from the event tracking unit 140 and in step 94 determinesthe types and amounts of physiologically active substances to be givenas medication by the medication unit 130 based on the organism internalpart information and the organism external information. In step 95, themedication unit 130 administers (doses) predetermined physiologicallyactive substances, for example insulin, based on the analysis result ofthe analysis engine 120.

As described above, the health management system 1 is a non-invasivehealth and vitality control platform having a continuous closed loop,includes a non-invasive spectrometer whose wavelength is programmable,further has a body activity and event tracking unit, a control unit, anda medication unit (drug delivery unit) in an integrated form, and iscapable of automatically carrying out automatic adjustment of themeasuring part. A non-invasive optical mass spectrometric technique isused for measurement based on blood. The monitor 10 that is the sensorplatform is a MEMS-based optical apparatus that has a tunable laser anduses highly permeable membrane tissue (thin film) at a part thatcontacts the human body.

This system 1 is used as a platform and has expandability in that newmethods (methods of treatment) and management methods can be downloadedand used.

1. (canceled)
 2. A sensor platform comprising: a tunable laser enginethat is capable of supplying a variable wavelength Stokes light and avariable wavelength pump light; an optical engine including a probe thatemits the Stokes light and the pump light on to at least part of anobservation region and receives a CARS light from the observationregion; and a detector for detecting the CARS light, and wherein theoptical engine includes optical paths for guiding the Stokes light andthe pump light from the tunable laser engine to the probe and the CARSlight from the probe to the detector, and the detector is wavelengthnon-selective detector and includes one or more optical elements thatacquire the CARS light from one or more components that are match one ormore wavelength conditions set by the Stokes light and the pump lighttuned with the tunable laser engine.
 3. The sensor platform according toclaim 2, wherein the detector includes at least one of a type ofphotodiode and a type including elements laid out in two dimensions. 4.The sensor platform according to claim 2, wherein the detector includes:a first type detector including a photodiode; a second type detectorincluding elements laid out in two dimensions; and an optical elementfor dividing and supplying the CARS light to the first and second typesof detector.
 5. The sensor platform according to claim 2, wherein thetunable laser engine, the optical engine, and the detector are packagedas chips respectively and are stacked.
 6. A monitor that includes thesensor platform according to claim 2 and monitors a state of an organisminternal part from a surface of the organism as the observation region.7. The monitor according to claim 6, wherein the tunable laser engine,the optical engine, and the detector are packaged as chips respectivelyand are stacked to be attached to the surface.
 8. The monitor accordingto claim 6, further comprising a signal processing engine that outputsfirst information showing the state of the organism internal part basedon detection results of the detector.
 9. The monitor according to claim8, wherein the first information includes a glucose concentration in ablood.
 10. A system comprising: a monitor according to claim 8; and adelivery system that provides a physiologically active substance to theorganism based on the first information.
 11. The system according toclaim 10 further comprising: a behavior monitor that acquires orpredicts an external state of the organism; and a controller thatcontrols an amount or type of physiologically active substance providedto the organism from the delivery system according to information fromthe behavior monitor in addition to the first information.